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Targeting Vacuolar H⁺-ATPases as a New Strategy against Cancer

¹ Department of Drug Research and Evaluation, Section of Pharmacogenetic, Drug Resistance and Experimental Therapeutic, Istituto Superiore di Sanità, Rome, Italy and ² National Laboratory for Oncogenes and Related Genes, WHO Collaborating Center for Research on Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China

Requests for reprints: Stefano Fais, Section of Pharmacogenetic, Drug Resistance and Experimental Therapeutic, Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy. Phone: 39-06-49903195; Fax: 39-06-49903691; E-mail: stefano.fais{at}iss.it or Wenxin Qin, National Laboratory for Oncogenes and Related Genes, WHO Collaborating Center for Research on Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China. Phone: 86-21-64436581; Fax: 86-21-64432142; E-mail: qinwenxin{at}smmail.cn.

Growing evidence suggests a key role of tumor acidic microenvironment in cancer development, progression, and metastasis. As a consequence, the need for compounds that specifically target the mechanism(s) responsible for the low pH of tumors is increasing. Among the key regulators of the tumor acidic microenvironment, vacuolar H⁺-ATPases (V-ATPases) play an important role. These proteins cover a number of functions in a variety of normal as well as tumor cells, in which they pump ions across the membranes. We discuss here some recent results showing that a molecular inhibition of V-ATPases by small interfering RNA in vivo as well as a pharmacologic inhibition through proton pump inhibitors led to tumor cytotoxicity and marked inhibition of human tumor growth in xenograft models. These results propose V-ATPases as a key target for new strategies in cancer treatment. [Cancer Res 2007;67(22):10627–30]

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